There are no vaccines available to prevent leishmaniasis and vector management strategies are currently unsustainable. As a consequence, antileishmanial chemotherapy is the only control measure available. Despite this fact, there are high rates of treatment failure to first line drugs in Latin America (between 5 and 75%). Although failure is frequently interpreted as a consequence of parasite drug resistance, the therapeutic response is multifactorial, and evidence supports a central role of host factors in treatment outcome. However, the underlying pharmacological, immunological and metabolic events, the associated regulatory mechanisms, and their variation among individuals are unknown. To optimize the usefulness of available chemotherapy for cutaneous leishmaniasis caused by Leishmania Viannia, this project seeks to identify host biomarkers associated with successful or failed treatment outcomes. We will use a comprehensive experimental design integrating targeted, hypothesis-driven methodological approaches including pharmacogenomic signatures of treatment failure, and state-of-the-art unbiased methodologies for biomarker discovery and functional validation host genes involved in host cell drug-responsiveness (metabolic profiling and shRNA library screening). This project specifically aims to identify pharmacological correlates of the therapeutic outcome. Results from this project will generate critical understanding of host-pathogen interactions in the context of antileishmanial chemotherapy and variations that occur within individuals, will inform on the mechanisms of drug responsiveness of host cells to antileishmanial drugs, and will allow the identification of biomarkers of treatment response. This investigation will challenge current approaches for the treatment of leishmaniasis by providing pre-clinical information of the usefulness of multi-marker biosignatures as predictive and/or prognostic tools of therapeutic outcome. It will also drive the development of innovative combination therapies that target intracellular drug bioavailability. Integration of these findings will provide the bases for improved disease management and control, based on early predictions of treatment response and optimized therapeutic interventions.